(A) Published European patent application No. 30,630 discloses a vast number of 7-acylamino-3-vinylcephalosporanic acid derivatives including, inter alia, those of the formula ##STR2## wherein R inter alia may be (lower) alkyl, (lower) alkenyl, (lower) alkynyl or carboxy (lower) alkyl. The compounds are prepared, inter alia by reaction of the corresponding 3-halomethyl compound with a triarylphosphine, followed by treatment with a base and reaction with formaldehyde. In each case, the final 3-substituent is the vinyl group. There is no disclosure or suggestion of a propenyl or a substituted propenyl moiety for the 3-substituent. There is also no disclosure or suggestion of an ester as pro-drug for oral use referring to the 4-carboxylic acid moiety. That compound wherein R is --CH.sub.2 CO.sub.2 H has been referred to in the literature as FK-027 and as cefixime. Related compounds in which R is --H or --CH.sub.3 are disclosed by Takaya, et al., in U.S. Pat. Nos. 4,559,334 and 4,585,860 patented Dec. 17, 1985 and Apr. 29, 1986 respectively.
(B) U.K. Patent Specification No. 1,399,086 contains a generic disclosure encompassing a vast number of cephalosporins of the formula ##STR3## wherein R is hydrogen or an organic group, R.sup.a is an etherifying monovalent organic group linked to the oxygen through a carbon atom, B is S or S=O, and P is an organic group. In one embodiment, P may be inter alia a vinyl group of the formula ##STR4## in which R.sup.3 and R.sup.4 independently may be hydrogen, nitrile, (lower)alkoxycarbonyl, or substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aromatic. However, the 2-aminothiazol-4-yl group is not identified as a possible R substituent and there is no disclosure or suggestion about an ester as pro-drug for oral use concerning the 4-carboxylic acid thereof. U.S. Pat. No. 3,971,778 and its divisionals Nos. 4,024,133, 4,024,137, 4,064,346, 4,033,950, 4,079,178, 4,091,209, 4,092,477, and 4,093,803 have similar disclosures.
(C) U.S. Pat. No. 4,307,233 discloses, inter alia, 3-vinyl cephalosporin derivatives of the formula ##STR5## in which R.sup.5 inter alia may be alkyl, vinyl, cyanomethyl or a protective group such as 2-methoxyprop-2-yl, and R.sup.3 and R.sup.4 are alkyl groups (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R.sup.3 and R.sup.4, taken together with the nitrogen to which they are attached, may form a saturated heterocyclic ring of 5 or 6 members, optionally containing another heteroatom selected from N, O and S, and optionally substituted by an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a substituted or an unsubstituted propenyl moiety for the 3-substituent and also no disclosure or suggestion concerning a pro-drug ester for oral use for the 4-carboxylic acid. Published United Kingdom patent application No. 2,051,062 is concordant thereto and has a similar disclosure.
(D) Published European patent application No. 53,537 discloses, inter alia, 3-vinylcephalosporin derivatives of the formula ##STR6## in which R.sub.5.sup.a and R.sub.5.sup.b are the same or different and are hydrogen or alkyl, or taken together, form an alkylene group containing 2 or 3 carbon atoms, R.sub.5.sup.c is an acid protecting group, R.sub.2 is an acid protecting group such as an ester, R.sub.3 and R.sub.4 are the same or different and are hydrogen, alkyl (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R.sub.3 and R.sub.4, taken together with the nitrogen to which they are attached, may form a saturated heterocyclic ring of 5 or 6 members, optionally containing another heteroatom selected from N, O and S, and optionally substituted by an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a substituted or an unsubstituted propenyl group for the 3-substituent and an ester of the 4-carboxylic acid for oral use.
(E) U.S. Pat. No. 4,307,116 discloses 3-thiovinylcephalosporins of the formula ##STR7## in which R.degree. is hydrogen, alkyl, vinyl or cyanomethyl, and R inter alia may be one of a vast number of heterocyclic rings. There is no disclosure or suggestion of a substituted or an unsubstituted propenyl moiety for the 3-substituent and also there is no disclosure or suggestion of an ester thereof for oral use.
(F) Published European patent application No. 53,074 generically discloses a vast number of 3-vinylcephalosporin derivatives of the formula ##STR8## wherein R.sub.1a .degree. (in one of several embodiments) may be ##STR9## in which R.sup.5 inter alia may be hydrogen, alkyl, vinyl, cyanomethyl, an oxime-protecting group such as trityl, etc., or a group of the formula ##STR10## in which R.sub.5.sup.a and R.sub.5.sup.b are the same or different, and may be hydrogen, alkyl or, taken together, an alkylene radical of 2 or 3 carbon atoms, and R.sub.5.sup.c is hydrogen or an acid-protecting radical; R.sub.2a .degree. is hydrogen or an acid-protecting radical such as methoxymethyl;
R.degree. (in one of several embodiments) may be a methyl group substituted by a 5- or 6-membered aromatic heterocyclic ring containing a single heteroatom, such as 2- or 3-pyridyl, 2- or 3-thienyl or 2- or 3-furyl; and
R.sub.3 is a group of the formula EQU R.sub.4 SO.sub.2 O--
in which R.sub.4 may be alkyl, trihalomethyl or optionally substituted phenyl. These compounds are stated to be intermediates in the preparation of compounds in which the 3-substituent is a group of the formula ##STR11## which are stated to have antibacterial activity. Although this patent includes the possibility of R.degree. being a methyl group substituted by an N-containing heterocyclic ring, in both the intermediates and final product (thus giving a heterocyclic-substituted propenyl moiety), the reference exemplifies R.degree. in the intermediates and final product only as methyl and further in both the intermediates and final product, the propenyl group must contain a second substituent (--O.sub.3 SR.sup.4 or --SR respectively). There is no disclosure or suggestion of an ester thereof for oral use.
(G) Published European patent application No. 53,538 discloses, inter alia, 3-vinylcephalosporin intermediates of the formula ##STR12## in which n is 0 or 1, R.sup.5 is hydrogen, alkyl, vinyl, cyanomethyl or an oxime-protecting group, and R.sup.3 is halogen.
(H) B. G. Christensen in U.S. Pat. No. 4,654,331 patented Mar. 31, 1987 discloses various (5-R-2-oxo-1,3-dioxolen-4-yl) methyl esters of certain cephalosporin antibiotics, and other physiological useful acids.